This application is the National Stage of International Application No. PCT/JP99/00703, filed Feb. 18, 1999.
The present invention relates to aminoguanidinehydrazone derivatives which are useful as a medicine, their production and use.
Sodium-proton (Naxe2x80x94H) exchange inhibitor comprising the aminoguanidinehydrazone derivative of the present invention is effective for the prevention and treatment of myocardial infarction and insufficiency accompanying therewith, arrhythmia, unstable angina, cardiac hypertrophy, restenosis after PTCA (percutaneous transluminal coronary angioplasty), hypertension and tissue injury accompanying therewith, etc.
On the other hand, Naxe2x80x94H exchange inhibitors, assumed to exhibit ameliorating and cell-protecting action in cell disorders under ischemic conditions, especially on the myocardium, are drawing attention in the field of therapeutic drugs for ischemic diseases.
Amiloride, an acylguanidine derivative and potassium-retaining diuretic, possesses weak activities for inhibiting Naxe2x80x94H exchange and potent activities for inhibiting sodium channel opening.
As Naxe2x80x94H exchange inhibitors, various kinds of acylguanidine derivatives are disclosed in Japanese Patent Unexamined Publication No. 228082/1994, WO 96/04241, EP 708091 and EP 708088, etc.
On the other hand, in EP456133, it is disclosed that a compound of the formula: 
wherein A is a chemical bond or xe2x80x94CH2xe2x80x94, X is a group of the formula: xe2x80x94C(xe2x95x90Y)xe2x80x94NR6R7, Y and Z are NH, R1 is hydrogen, lower alkyl, hydroxy group, lower alkoxy or halogen atom, R2 is hydrogen or lower alkyl, R3, R4 and R6 are hydrogen, and R5 and R7 are independently hydrogen, lower alkyl or hydroxy group; is useful as anti-cancer agent or agent for treating protozoiasis.
In addition, in Japanese Patent Publication No. 239454/1985, it is disclosed that a compound of the formula: 
wherein R is hydrogen, halogen atom, etc., A is a chemical bond, CR4R5, CR6R7xe2x80x94CR8R9, CR10R11xe2x80x94CR12R13xe2x80x94CR14R15, etc., X is CR1R2, O, S(O)n (n=0,1,2), NR3, etc., and R1 to R15 are independently hydrogen, an optionally substituted aromatic or hetero-aromatic group, etc.; shows digitalis agonistic or antagonistic activity.
Amiloride causes hypotension and salt excretion, which activities are undesirable for the treatment of heart rate disorder, by its potent activities for inhibiting sodium channel opening.
The present invention is to provide a Naxe2x80x94H exchange inhibitor which is effective for the prevention and treatment of myocardial infarction and insufficiency accompanying therewith, arrhythmia, unstable angina, cardiac hypertrophy, restenosis after PTCA, hypertension and tissue injury accompanying therewith, etc.
The present inventors studied various compounds having activities for inhibiting Naxe2x80x94H exchange, and as a result, for the first time synthesized a novel compound of the formula (I): 
wherein the ring A is an optionally substituted 5- to 6-membered aromatic heterocyclic ring, the ring B an optionally substituted 5- to 6-membered aromatic homocyclic ring or an optionally substituted 5- to 6-membered aromatic heterocyclic ring, R1 is a hydrogen atom, a hydroxy group or a lower alkyl group, and n is 0 or 1, or a salt thereof [hereinafter referred to as Compound (I)], and found that said Compound (I) unexpectedly exhibits excellent activities for inhibiting Naxe2x80x94H exchange. The present inventors accomplished the present invention based on this finding.
Accordingly, the present invention relates to
(1) Compound (I);
(2) a pro-drug of Compound (I);
(3) a compound of the formula: 
xe2x80x83wherein each symbol is as defined in the above (1) or a salt thereof;
(4) a compound of the formula: 
xe2x80x83wherein each symbol is as defined in the above (1) or a salt thereof;
(5) Compound (I) as described in the above (1), wherein the aromatic heterocyclic ring is an aromatic heterocyclic ring containing 1 to 3 hetero-atoms selected from the class consisting of oxygen atom, sulfur atom and nitrogen atom;
(6) Compound (I) as described in the above (1), wherein the ring A is pyridine ring, pyridazine ring, pyrrole ring, pyrazole ring, furan ring, thiophene ring, isoxazole ring or pyrimidine ring, each of which may be substituted;
(7) Compound (I) as described in the above (1), wherein the ring B is pyridine ring, pyrrole ring, furan ring, thiophene ring or benzene ring, each of which may be substituted;
(8) Compound (I) as described in the above (1), wherein R1 is a hydrogen atom;
(9) Compound (I) as described in the above (1), wherein n is 1;
(10) (S)-(xe2x88x92)-7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a salt thereof;
(11) (xc2x1)-7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a salt thereof;
(12) (S)-(xe2x88x92)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a salt thereof;
(13) (xc2x1)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a salt thereof;
(14) (xc2x1)-7-(2,5-dichlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline or a salt thereof;
(15) (xc2x1)-7-(5-chloro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a salt thereof;
(16) (xc2x1)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a salt thereof;
(17) (xc2x1)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a salt thereof;
(18) (xc2x1)-7-(5-chloro-2-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline or a salt thereof;
(19) (xc2x1)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline or a salt thereof;
(20) (xc2x1)-7-(5-chloro-2-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline or a salt thereof;
(21) a pharmaceutical composition comprising Compound (I) as described in the above (1) or a salt thereof;
(22) a composition of the above (21), which is for Naxe2x80x94H exchange inhibitor;
(23) a composition of the above (21), which is for the prevention or treatment of ischemic cardiac disease;
(24) a composition of the above (23), wherein the ischemic cardiac disease is myocardial infarction, unstable angina or arrhythmia;
(25) a composition of the above (21), which is for the prevention or treatment of cardiac insufficiency;
(26) use of Compound (I) as described in the above (1) or a salt thereof for manufacturing Naxe2x80x94H exchange inhibitor;
(27) use of Compound (I) as described in the above (1) or a salt thereof for manufacturing a pharmaceutical composition for the prevention or treatment of ischemic cardiac disease;
(28) use of Compound (I) as described in the above (1) or a salt thereof for manufacturing a pharmaceutical composition for the prevention or treatment of cardiac insufficiency;
(29) a method for inhibiting Naxe2x80x94H exchange in a mammal which comprises administering to said mammal an effective amount of Compound (I) as described in the above (1) or a salt thereof;
(30) a method for preventing or treating ischemic cardiac disease in a mammal which comprises administering to said mammal an effective amount of Compound (I) as described in the above (1) or a salt thereof;
(31) a method for preventing or treating cardiac insufficiency in a mammal which comprises administering to said mammal an effective amount of Compound (I) as described in the above (1) or a salt thereof; and
(32) a method for producing a compound of the formula (I): 
xe2x80x83wherein each symbol is as defined below, or a salt thereof, which comprises reacting a compound of the formula (II): 
xe2x80x83wherein the ring A is an optionally substituted 5- to 6-membered aromatic heterocyclic ring, the ring B an optionally substituted 5- to 6-membered aromatic homocyclic ring or an optionally substituted 5- to 6-membered aromatic heterocyclic ring, and n is 0 or 1, or a salt thereof with a compound of the formula (III):
H2Nxe2x80x94Nxe2x95x90C(NH2)(NHR1)
xe2x80x83wherein R1 is a hydrogen atom, a hydroxy group or a lower alkyl group, or a salt thereof; etc.
In the above formula (I), the ring A is an optionally substituted 5- to 6-membered aromatic heterocyclic ring.
Examples of the aromatic heterocyclic ring in the xe2x80x9coptionally substituted 5- to 6-membered aromatic heterocyclic ringxe2x80x9d represented by A include, for example, an aromatic heterocyclic ring containing at least one hetero-atom (preferably 1 to 3 hetero-atoms, more preferably 1 to 2 hetero-atoms) consisting of 1 to 3 kinds (preferably 1 to 2 kinds) of hetero-atoms selected from an oxygen atom, a sulfur atom, a nitrogen atom, etc., as an atom constituting ring structure (ring atom).
Examples of said xe2x80x9caromatic heterocyclic ringxe2x80x9d include, for example, a 5- to 6-membered aromatic heterocyclic ring, etc. such as furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc.), etc.
Among others, a 5- to 6-membered aromatic heterocyclic ring containing 1 to 3 hetero-atoms (preferably 1 to 2 hetero-atoms) selected from an oxygen atom, a sulfur atom and a nitrogen atom is preferable, and preferred examples of the ring A include a pyridine ring, a pyridazine ring, a pyrrole ring, a pyrazole ring, a furan ring, a thiophene ring, an isoxazole ring, a pyrimidine ring (preferably, a 5- to 6-membered nitrogen-containing aromatic heterocyclic ring which contains 1-2 nitrogen atoms, etc. such as a pyridine ring, a pyridazine ring, a pyrrole ring, a pyrazole ring, etc.).
In the above formula (I), the ring B is an optionally substituted 5- to 6-membered aromatic homo- or hetero-cyclic ring.
Examples of the xe2x80x9coptionally substituted 5- to 6-membered aromatic homocyclic ringxe2x80x9d represented by B include an optionally substituted benzene ring, etc.
Examples of the aromatic heterocyclic ring in the xe2x80x9coptionally substituted 5- to 6-membered aromatic heterocyclic ringxe2x80x9d represented by B include, for example, an aromatic heterocyclic ring containing at least one hetero-atom (preferably 1 to 3 hetero-atoms, more preferably 1 to 2 hetero-atoms) consisting of 1 to 3 kinds (preferably 1 to 2 kinds) of hetero-atoms selected from an oxygen atom, a sulfur atom, a nitrogen atom, etc., as an atom constituting ring structure (ring atom).
Examples of said xe2x80x9caromatic heterocyclic ringxe2x80x9d include, for example, a 5- to 6-membered aromatic heterocyclic ring, etc. such as furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc.), etc. Among others, a 5- to 6-membered aromatic heterocyclic ring containing 1 to 3 hetero-atoms (preferably 1 to 2 hetero-atoms) selected from an oxygen atom, a sulfur atom and a nitrogen atom is preferable.
Preferred examples of the ring B include a 5- to 6-membered aromatic homo- or hetero-cyclic ring which may contain one hetero-atom selected from an oxygen atom, a sulfur atom and a nitrogen atom, etc. such as a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, a pyridine ring (preferably a benzene ring, a furan ring, a thiophene ring, etc.), etc.
Both of the ring A and the ring B may be substituted with 1 to 4 (preferably 1 to 2) identical or different substituents selected from, for example, (1) a halogen atom, (2) a hydroxy group, (3) a nitro group, (4) a cyano group, (5) an optionally substituted lower alkyl group, (6) an optionally substituted lower alkenyl group, (7) an optionally substituted lower alkynyl group, (8) an optionally substituted lower aralkyl group, (9) an optionally substituted lower alkoxy group, (10) an optionally substituted mercapto group, (11) an optionally substituted amino group, (12) a carboxyl group optionally esterified or amidated, (13) an optionally substituted sulfonyl group, (14) an optionally substituted acyl group and (15) an optionally substituted phenyl group, at any possible position; and (16) adjoining two of these substituents may bind to each other to form a divalent hydrocarbon group; and a nitrogen atom of the ring A and the ring B may be oxidized.
In addition, when the ring A or the ring B is a nitrogen-containing aromatic heterocyclic ring having a hydroxy group as a substituent such as 2-oxypyridine, etc., the ring A or the ring B may be a nitrogen-containing aromatic heterocyclic ring having a oxo group such as xcex1-pyridone, etc. (which is equivalent to a nitrogen-containing aromatic heterocyclic ring having a hydroxy group as a substituent, in chemical structure), and when the ring A or the ring B is a nitrogen-containing aromatic heterocyclic ring having a oxo group, the ring A or the ring B may have a substituent similar to that for the above-mentioned ring A or ring B, on the nitrogen atom.
Examples of the halogen atom as (1) include, for example, chlorine, bromine, fluorine, iodine, etc.
Examples of the lower alkyl group in the optionally substituted lower alkyl group as (5) include, for example, a C1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, s-butyl, pentyl, hexyl, etc.), etc.
Said lower alkyl group may be substituted with 1 to 3 identical or different substituents selected from, for example, a halogen atom (for example, chlorine, bromine, fluorine, iodine, etc.), a hydroxy group, a nitro group, a cyano group, a lower (C1-6) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.), a halogeno lower (C1-6) alkoxy group (for example, CF3O, CHF2O, etc.), etc., at any possible position.
Examples of the lower alkenyl group in the optionally substituted lower alkenyl group as (6) include, for example, a C2-6 alkenyl group, etc. such as vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc.
Said lower alkenyl group may be substituted with 1 to 3 identical or different substituents selected from, for example, a halogen atom (for example, chlorine, bromine, fluorine, iodine, etc.), a hydroxy group, a nitro group, a cyano group, a lower (C1-6) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.), a halogeno lower (C1-6) alkoxy group (for example, CF3O, CHF2), etc.), etc., at any possible position.
Examples of the lower alkynyl group in the optionally substituted lower alkynyl group as (7) include, for example, a C2-6 alkynyl group such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.
Said lower alkynyl group may be substituted with 1 to 3 identical or different substituents selected from, for example, a halogen atom (for example, chlorine, bromine, fluorine, iodine, etc.), a hydroxy group, a nitro group, a cyano group, a lower (C1-6) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.), a halogeno lower (C1-6) alkoxy group (for example, CF3O, CHF2O, etc.), etc., at any possible position.
Examples of the lower aralkyl group in the optionally substituted lower aralkyl group as (8) include, for example, a C7-10 aralkyl group (preferably, phenyl-C1-6 alkyl group, etc.), etc. such as benzyl, phenethyl, etc.
Said lower aralkyl group may be substituted with 1 to 3 identical or different substituents selected from, for example, a halogen atom (for example, chlorine, bromine, fluorine, iodine, etc.), a hydroxy group, a nitro group, a cyano group, a lower (C1-6) alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc.), a halogeno lower (C1-6) alkyl group (for example, CF3, CF2CF3, CH2F, CHF2, etc.), a lower (C1-6) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.), a halogeno lower (C1-6) alkoxy group (for example, CF3O, CHF2O, etc.), etc., at any possible position.
Examples of the lower alkoxy group in the optionally substituted lower alkoxy group as (9) include, for example, a C1-6 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.), etc.
Said lower alkoxy group may be substituted with 1 to 3 identical or different substituents selected from, for example, a halogen atom (for example, chlorine, bromine, fluorine, iodine, etc.), a hydroxy group, a nitro group, a cyano group, a lower (C1-6) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.), a halogeno lower (C1-6) alkoxy group (for example, CF3O, CHF2O, etc.), etc., at any possible position.
Examples of the optionally substituted mercapto group as (10) include, for example, an optionally substituted C1-6 alkylthio group (for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, s-butylthio, t-butylthio, pentylthio, isopentyloxy, neopentylthio; hexylthio, etc.), etc.
Said C1-6 alkylthio group may be substituted with 1 to 3 identical or different substituents selected from, for example, a halogen atom (for example, chlorine, bromine, fluorine, iodine, etc.), a hydroxy group, a nitro group, a cyano group, a lower (C1-6) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.), a halogeno lower (C1-6) alkoxy group (for example, CF3O, CHF2O, etc.), etc., at any possible position.
Examples of the optionally substituted amino group as (11) include, for example, amino groups which may be substituted with 1 or 2 identical or different substituents selected from lower (C1-6) alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc.), lower (C1-6) alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, hexyloxy, etc.), halogeno lower (C1-6) alkyl (for example, CF3, CF3CF2, CH2F, CHF2, etc.), lower (C3-6)cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), hydroxy group, carbamoyl, phenyl, phenyl-lower (C1-6) alkyl (for example, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, etc.), lower (C1-6) alkanoyl (for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, etc.), C3-6 cycloalkyl-carbonyl (for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), benzoyl, phenyl-C2-6 alkanoyl (for example, phenylacetyl, phenylpropionyl, etc.), lower (C1-6) alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), phenoxycarbonyl, phenyl-C1-6 alkoxy-carbonyl (for example, benzyloxycarbonyl, phenylethoxycarbonyl, etc.), lower (C1-6) alkylsulfinyl (for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, s-butylsulfinyl, t-butylsulfinyl, pentylsulfinyl, hexylsulfinyl, etc.), C3-6 cycloalkylsulfinyl (for example, cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, etc.), phenylsulfinyl, lower (C1-6) alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, t-butylsulfonyl, s-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), C3-6 cycloalkylsulfonyl (for example, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.), lower (C1-6) alkoxysulfonyl (for example, methoxysulfonyl, ethoxysulfonyl, propoxysulfonyl, isopropoxysulfonyl, butoxysulfonyl, isobutoxysulfonyl, s-butoxysulfonyl, t-butoxysulfonyl, pentyloxysulfonyl, hexyloxysulfonyl, etc.), phenylsulfonyl, etc.
Also, two of the substituents may form a cyclic amino group in cooperation with a nitrogen atom, and examples of the cyclic amino group include, for example, pyrrolidino, piperidino, morpholino, thiomorpholino, etc.
Each of the optionally substituted amino groups as exemplified above may be substituted with 1 to 3 identical or different substituents selected from, for example, a halogen atom (for example, chlorine, bromine, fluorine, iodine, etc.), a hydroxy group, a nitro group, a cyano group, a lower (C1-6) alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc.), a halogeno lower (C1-6) alkyl group (for example, CF3, CF2CF3, CH2F, CHF2, etc.), a lower (C1-6) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.), a halogeno lower (C1-6) alkoxy group (for example, CF3O, CHF2O, etc.), etc., at any possible position.
Examples of the esterified carboxyl group in the carboxyl group optionally esterified or amidated as (12) include, for example, a lower (C1-6) alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, etc.), a C3-6 cycloalkoxy-carbonyl (for example, cyclopropoxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, etc.), a phenyl-C1-6 alkoxy-carbonyl (for example, benzyloxycarbonyl, phenyloxycarbonyl, etc.), a nitroxy-C1-6 alkoxy-carbonyl (for example, 2-nitroxyethoxycarbonyl, 3-nitroxypropoxycarbonyl, etc.), etc.
Examples of the amidated carboxyl group include a carbamoyl, a N-mono-lower (C1-6) alkylcarbamoyl (for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, s-butylcarbamoyl, t-butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, etc.), a N,N-di-lower (C1-6) alkylcarbamoyl (for example, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N-dibutylcarbamoyl, etc.), a C3-6 cycloalkyl-carbamoyl (for example, cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl, etc.), a phenyl-C1-6 alkyl-carbamoyl (for example, benzylcarbamoyl, phenethylcarbamoyl, etc.), a nitroxy-C1-6 alkylamino-carbonyl (for example, 2-nitroxyethylcarbamoyl, 3-nitroxypropylcarbamoyl, etc.), a cyclic aminocarbonyl (for example, morpholinocarbonyl, piperidinocarbonyl, pyrrolidinocarbonyl, thiomorpholinocarbonyl, etc.), an anilinocarbonyl, etc.
Each of the xe2x80x9ccarboxyl group optionally esterified or amidatedxe2x80x9d as exemplified above may be substituted with 1 to 3 identical or different substituents selected from, for example, a halogen atom (for example, chlorine, bromine, fluorine, iodine, etc.), a hydroxy group, a nitro group, a cyano group, a lower (C1-6) alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc.), a halogeno lower (C1-6) alkyl group (for example, CF3, CF2CF3, CH2F, CHF2, etc.), a lower (C1-6) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.), a halogeno lower (C1-6) alkoxy group (for example, CF3O, CHF2O, etc.), etc. at any possible position.
Examples of the optionally substituted sulfonyl group as (13) include, for example, a lower (C1-6) alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), a C3-6 cycloalkylsulfonyl (for example, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.), a phenyl-C1-6 alkylsulfonyl (for example, benzylsulfonyl, phenethylsulfonyl, etc.), a lower (C1-6) alkoxysulfonyl (for example, methoxysulfonyl, ethoxysulfonyl, propoxysulfonyl, isopropoxysulfonyl, butoxysulfonyl, isobutoxysulfonyl, s-butoxysulfonyl, t-butoxysulfonyl, pentyloxysulfonyl, hexyloxysulfonyl, etc.), a C3-6 cycloalkyloxysulfonyl (for example, cyclopropoxysulfonyl, cyclobutyloxysulfonyl, cyclopentyloxysulfonyl, cyclohexyloxysulfonyl, etc.), a phenyl-C1-6alkoxysulfonyl (for example, benzyloxysulfonyl, phenethyloxysulfonyl, etc.), a sulfamoyl, a lower (C1-6) alkylaminosulfonyl (for example, methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, butylaminosulfonyl, isobutylaminosulfonyl, s-butylaminosulfonyl, t-butylaminosulfonyl, pentylaminosulfonyl, hexylaminosulfonyl, etc.), a C3-6 cycloalkylaminosulfonyl (for example, cyclopropylaminosulfonyl, cyclobutylaminosulfonyl, cyclopentylaminosulfonyl, cyclohexylaminosulfonyl, etc.), a phenyl-C1-6 alkylaminosulfonyl (for example, benzylaminosulfonyl, phenethylaminosulfonyl, etc.), a cyclic aminosulfonyl (for example, morpholinosulfonyl, piperidinosulfonyl, pyrrolidinosulfonyl, thiomorpholinosulfonyl, etc.), a nitroxy-C1-6 alkylamino-sulfonyl (for example, 2-nitroxyethylaminosulfonyl, 3-nitroxypropylaminosulfonyl, etc.), an anilinosulfonyl, etc.
Each of the xe2x80x9coptionally substituted sulfonyl groupxe2x80x9d as exemplified above may be substituted with 1 to 3 identical or different substituents selected from, for example, a halogen atom (for example, chlorine, bromine, fluorine, iodine, etc.), a hydroxy group, a nitro group, a cyano group, a lower (C1-6) alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc.), a halogeno lower (C1-6) alkyl group (for example, CF3, CF2CF3, CH2F, CHF2, etc.), a lower (C1-6) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.), a halogeno lower (C1-6) alkoxy group (for example, CF3O, CHF2O, etc.), etc., at any possible position.
Examples of the lower acyl group as (14) include, for example, a lower acyl group derived from a carboxylic acid, a sulfinic acid, a sulfonic acid, etc.
Here, examples of the lower acyl group derived from a carboxylic acid include, for example, a lower (C1-6) alkyl-carbonyl (alkanoyl) (for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, etc.), a C3-6 cycloalkyl-carbonyl (for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), benzoyl, etc.
Examples of the lower acyl group derived from a sulfinic acid include, for example, a lower (C1-6) alkylsulfinyl (for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, s-butylsulfinyl, t-butylsulfinyl, pentylsulfinyl, hexylsulfinyl, etc.), a C3-6 cycloalkylsulfinyl (for example, cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfonyl, etc.), phenylsulfinyl, etc.
Examples of the lower acyl group derived from a sulfonic acid include, for example, a lower (C1-6) alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), a C3-6 cycloalkylsulfonyl (for example, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.), phenylsulfonyl, etc.
Each of the xe2x80x9clower acyl groupxe2x80x9d as exemplified above may be substituted with 1 to 3 identical or different substituents selected from, for example, a halogen atom (for example, chlorine, bromine, fluorine, iodine, etc.), a hydroxy group, nitro group, a cyano group, a lower (C1-6) alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc.), a halogeno lower (C1-6) alkyl group (for example, CF3, CF2CF3, CH2F, CHF2, etc.), a lower (C1-6) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.), a halogeno lower (C1-6) alkoxy group (for example, CF3O, CHF2O, etc.), etc., at any possible position.
The optionally substituted phenyl group as (15) may be substituted with 1 to 3 identical or different substituents selected from, for example, a halogen atom (e.g. chlorine, bromine, fluorine, iodine, etc.), hydroxy group, nitro group, cyano group, lower (C1-6) alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc.), halogeno-lower (C1-6) alkyl group (e.g. CF3, CF2CF3, CH2F, CHF2, etc.), lower (C1-6) alkoxy group (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.), halogeno-lower (C1-6) aalkoxy group (e.g. CF3O, CHF2O, etc.), etc., at any possible position.
Examples of the divalent hydrocarbon group as (16) include, for example, a group of the formula:
xe2x80x83xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94CH2,
xe2x80x94(CH2)a-
(a is 3 or 4), etc.
Here, the above-mentioned divalent hydrocarbon group forms a 5- to 6-membered ring with two atoms constituting the ring A, and said 5- to 6-membered ring may be substituted with 1 to 3 identical or different substituents selected from, for example, lower (C1-6) alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc.), halogen atom (for example, chlorine, bromine, fluorine, iodine, etc.), lower (C1-6) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.), halogeno lower (C1-6) alkyl group (for example, CF3, CF2CF3, CH2F, CHF2, etc.), halogeno lower (C1-6) alkoxy group (for example, CF3O, CF2CF3O, CH2FO, CHF2O, etc.), lower (C1-6) alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, etc.), cyano group, nitro group, hydroxy group, etc., at any possible position.
As the substituent for the ring A, a lower (C1-6) alkyl group (preferably methyl) optionally halogenated, a lower (C1-6) alkoxy group (preferably methoxy) optionally halogenated, etc. are preferable.
As the ring A, a group of the formula: 
wherein the ring Axe2x80x2 is an optionally substituted 5- to 6-membered aromatic heterocyclic ring (preferably, pyridine, pyrazole, pyrrole, furan, more preferably, pyridine, pyrazole) which may have an optional substituent in addition to the group Ra, Z is an oxygen atom, a sulfur atom or a nitrogen atom, and Ra is the above-mentioned substituent for the ring A (preferably, lower (C1-6) alkyl group optionally halogenated, lower (C1-6) alkoxy group optionally halogenated, etc.) is preferable.
As the substituent for the ring B, halogen atom (preferably chlorine), lower (C1-6) alkyl group (preferably methyl) optionally halogenated, hydroxy group, lower (C1-6) alkoxy group (preferably methoxy) optionally halogenated, etc. are preferable.
As the ring B, a group of the formula: 
wherein the ring Bxe2x80x2 is an optionally substituted 5- to 6-membered aromatic homo- or hetero-cyclic ring (preferably, benzene, thiophene) in addition to the group Rb, Y is a carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom and Rb is hydrogen atom or the above-mentioned substituent for the ring B (preferably halogen atom, lower (C1-6) alkyl group optionally halogenated, hydroxy group, lower (C1-6) alkoxy group optionally halogenated, etc.) is preferable.
In the above formula (I), R1 is a hydrogen atom, a hydroxy group or a lower alkyl group (for example, lower (C1-6) alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc.), preferably methyl). As the group R1, hydrogen atom, hydroxy group and methyl group are preferable, hydrogen atom and hydroxy group are more preferable, and in particular, hydrogen atom is preferable.
In the above formula (I), n is 0 or 1 (preferably, 1).
As the Compound (I),
(S)-(xe2x88x92)-7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
(xc2x1)-7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
(S)-(xe2x88x92)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
(xc2x1)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
(xc2x1)-7-(2-bromophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
7-(3,5-dichlorothiophen-2-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
7-(2,5-dichlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
6-(2,5-dichlorothiophen-3-yl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydroindazol;
(xc2x1)-7-(2,5-dichlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline;
(xc2x1)-7-(5-chloro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
(xc2x1)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
(xc2x1)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
(xc2x1)-7-(5-chloro-2-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
(xc2x1)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline
(xc2x1) -7-(5-chloro-2-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline;
or a salt thereof are preferable.
Among others,
(S)-(xe2x88x92)-7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
(xc2x1)-7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
(S)-(xe2x88x92)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
(xc2x1)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
(xc2x1)-7-(2,5-dichlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline;
(xc2x1)-7-(5-chloro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
(xc2x1)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
(xc2x1)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
(xc2x1)-7-(5-chloro-2-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline;
(xc2x1)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline;
(xc2x1)-7-(5-chloro-2-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline or a salt thereof are preferable.
The pro-drug of the compound of the formula (I) means a compound which is converted to the compound of the formula (I) under the physiological conditions or with a reaction due to an enzyme, an gastric acid, etc. in the living body, that is, a compound which is converted to the compound of the formula (I) with oxidation, reduction, hydrolysis, etc. according to an enzyme; a compound which is converted to the compound of the formula (I) with gastric acid, etc.; etc.
Examples of the pro-drug of the compound of the formula (I) include a compound wherein an amino group of the compound of the formula (I) is substituted with acyl, alkyl, phosphoric acid, etc. (e.g. a compound wherein an amino group of the compound of the formula (I) is substituted with eicosanoyl, alanyl, pentylaminocarbonyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl, tert-butyl, etc.); a compound wherein an hydroxy group of the compound of the formula (I) is substituted with acyl, alkyl, phosphoric acid, boric acid, etc. (e.g. a compound wherein an hydroxy group of the compound of the formula (I) is substituted with acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl, dimethylaminomethylcarbonyl, etc.); a compound wherein a carboxyl group of the compound of the formula (I) is modified with ester, amide, etc. (e.g. a compound wherein a carboxyl group of the compound of the formula (I) is modified with ethylester, phenylester, carboxymethylester, dimethylaminomethylester, pivaloyloxymethylester, ethoxycarbonyloxyethylester, phthalidylester, (5-methyl-2-oxo1,3-dioxolen-4-yl)methylester, cyclohexyloxycarbonylethylester, methylamide, etc.); etc. These pro-drugs can be produced by per se known method from the compound of the formula (I).
The pro-drug of the compound of the formula (I) may be a compound which is converted into the compound of the formula (I) under the physiological conditions as described in xe2x80x9cPharmaceutical Research and Developmentxe2x80x9d, Vol. 7 (Drug Design) pages 163-198 published in 1990 by Hirokawa Publishing Co. (Tokyo, Japan).
Examples of the salt of Compound (I) or its synthetic intermediates include a pharmaceutically acceptable salt, for example, an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc., an organic acid salt such as acetate, tartrate, citrate, fumarate, maleate, toluenesulfonate, methanesulfonate, etc., a salt with an amino acid such as an aspartic acid, a glutamic acid, a pyroglutamic acid, an arginine, a lysine, ornithine, etc., a metal salt such as sodium salt, potassium salt, calcium salt, aluminum salt, etc., a salt with a base such as triethylamine salt, guanidine salt, ammonium salt, hydrazine salt, quinine salt, cinchonine salt, etc., etc.
Compound (I) may be used as a hydrate.
When Compound (I) exists as configuration isomer, diastereomer, conformer, etc., it is possible to isolate individual isomers with per se known separation and purification method, if desired.
Compound (I) has geometrical isomerism at the position of a hydrazone structure based on configuration of a fused heterocyclic ring including the ring A, and exists as E-isomer, Z-isomer or a mixture thereof.
Further, when R1 is a hydroxy group or a lower alkyl group, Compound (I) has geometrical isomerism based on double bond of a guanidino group, and exists as E-isomer, Z-isomer or a mixture thereof.
In Compound (I), the following individual isomers and a mixture thereof are included. 
Also, Compound (I) has an optical isomer based on an asymmetric carbon existing at the position where the ring B is substituted, etc., and exists as R-isomer, S-isomer or a mixture thereof in connection with individual asymmetric carbon. It can be separated into individual R-isomer and S-isomer with usual optical resolution and individual optical isomers and a mixture thereof are included by Compound (I). For example, Compound (I) includes the following individual optical isomers and a mixture thereof. 
In the present specification the starting material or a, synthesis intermediate of Compound (I), or a salt, thereof, is also referred to as the starting material or synthesis intermediate of Compound (I), with xe2x80x9cor a salt thereofxe2x80x9d omitted.
In addition, Compound (I) is equivalent to Compound (Ia) and Compound (Ib) in view of its chemical structure. 
Compound (I) can be produced by a method described in e.g. Japanese Patent Unexamined Publication No. 309837/1995, Japanese Patent Application No. 224945/1997 (Japanese Patent Unexamined Publication No. 114753/1998), Japanese Patent Application No. 224946/1997 (Japanese Patent Unexamined Publication No. 114744/1998), etc. or a method similar thereto, and also by reacting a compound of the formula 
wherein each symbol is as defined above or a salt thereof with an aminoguanidine compound of the formula
H2Nxe2x80x94Nxe2x95x90C(NH2)(NHR1)xe2x80x83xe2x80x83(III)
wherein each symbol is as defined above or a salt thereof, etc.
Compound (III) is usually used at about 1 to about 2 mol per mol of Compound (II). This reaction can be facilitated by the addition of triethylamine, pyrrolidine, sodium acetate, boron trifluoride diethylether, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, etc. as a catalyst, which is added at about {fraction (1/10)} to about 10 mol, if necessary.
For example, this condensation reaction can be carried out in an inert solvent such as methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethylether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetic acid, pyridine, water, etc., or a mixed solvent thereof. The reaction is carried out in a temperature range from about 0xc2x0 C. to about 180xc2x0 C.
Compound (II) and Compound (III) used as the starting material can be produced by a known method or a method similar thereto. For example, they can be produced by the following Reaction Scheme I or Reference Example shown below.
Reaction Scheme I 
In the above-mentioned Reaction Scheme I, R2 to R19 and R22 to R24 are independently a substituent for the above-mentioned ring A, and M1 to M6 are independently a leaving group.
Each process of the Reaction Scheme I is hereinafter described in detail.
(Process 1)
Ketone Compound (IV) can be produced by reacting Compound (XIII) with Compound (XIV), followed by oxidation of a hydroxy group and cyclization. In addition, if necessary, the cyclized product is reacted with Compound (XV) in the presence of a base to produce Compound (IV) wherein the substituent R4 is introduced into the ketone compound.
This condensation reaction can be carried out in an inert solvent such as tetrahydrofuran, diethylether, dimethoxyethane, methanol, ethanol, hexane, toluene, benzene, dichloromethane, acetic acid, etc., or a mixed solvent thereof, and in a temperature range from about 0xc2x0 C. to about 130xc2x0 C. The reaction time is about 1 hour to about 100 hours. Compound (XIV) is usually used at about 1 to about 2 mol per mol of Compound (XIII). This reaction can be facilitated by the addition of molecular sieves, etc.
Oxidation, ring-closure reaction (cyclization reaction) and dehydration reaction after the above reaction can be carried out by a known method. For example, when equivalent mol to about twice mol of aromatic halide is used as an oxidizing agent, the reaction is carried out in the presence of about 0.1 to about 20 mol % of transit metal catalyst and equivalent mol to about twice mol of base, in an inert solvent such as tetrahydrofuran, dimethoxyethane, dimethylformamide, N-methylpyrrolidone, hexane, toluene, benzene, dichloromethane, chloroform, etc., or a mixed solvent thereof, and in a temperature range from about 50xc2x0 C. to about 200xc2x0 C. The reaction time is about 1 hour to about 50 hours. Examples of the aromatic halide used as an oxidizing agent include bromobenzene, bromomesitylene, o-bromotoluene, etc. Examples of the transit metal catalyst include nickel, palladium, platinum, platinum, ruthenium, etc. This reaction can be facilitated by the addition of palladium catalyst such as tetrakis(triphenylphosphine)palladium, etc. As the base, potassium carbonate, sodium hydride, etc. can be employed. In addition, this reaction is preferably carried out in an inert gas (e.g., nitrogen, argon) atmosphere.
The reaction with Compound (XV) can be carried out in an inert solvent such as tetrahydrofuran, dimethoxyethane, dimethylformamide, N-methylpyrrolidone, hexane, toluene, benzene, dichloromethane, chloroform, etc., or a mixed solvent thereof, and in a temperature range from about 0xc2x0 C. to about 150xc2x0 C. The reaction time is about 1 hour to about 50 hours. As the base, triethylamine, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc. can be employed. Compound (XV) is usually used at about 1 to about 2 mol per mol of Compound (XIII).
(Process 2)
Compound (XIII) is reacted with an aminating agent to produce an enamine derivative, which is reacted with Compound (XVI) (wherein R20 is xe2x80x94CH2COCH3, xe2x80x94Cxe2x89xa1CH, xe2x80x94CH2CH(OMe)2, etc.) to produce ketone Compound (V). Also, if necessary, in the presence of an aminating agent, Compound (XIII) is reacted with Compound (XVI) to produce ketone Compound (V), without isolating the enamine derivative.
Said amination is carried out in the presence of an aminating agent such as ammonium acetate, etc., in an inert solvent such as methanol, ethanol, benzene, toluene, chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethylether, hexane, ethyl acetate, dimethylformamide, etc., or a mixed solvent thereof, and in a temperature range from about 0xc2x0 C. to about 150xc2x0 C. The reaction time is about 1 hour to about 100 hours. The aminating agent is usually used at about 1 to about 10 mol per mol of Compound (XIII).
Condensation. and cyclization reaction can be carried out in an inert solvent such as methanol, ethanol, benzene, toluene, chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethylether, hexane, ethyl acetate, dimethylformamide, dimethylsulfoxide, etc., or a mixed solvent thereof, and in a temperature range from about 0xc2x0 C. to about 150xc2x0 C. The reaction time is about 1 hour to about 50 hours. Compound (XVI) is usually used at about 1 to about 5 mol per mol of Compound (XIII).
In addition, when the enamine derivative is not isolated, said amination is carried out in the presence of an aminating agent such as ammonium acetate, etc., according to a method similar to that described above.
(Process 3)
Compound (XIII) is reacted with Compound (XVII), followed by cyclization and oxidation to produce ketone Compound (V).
This condensation reaction can be carried out in an inert solvent such as tetrahydrofuran, diethylether, dimethoxyethane, methanol, ethanol, hexane, toluene, benzene, dichloromethane, etc., or a mixed solvent thereof, and in a temperature range from about 0xc2x0 C. to about 130xc2x0 C. The reaction time is about 1 hour to about 100 hours. Compound (XVII) is usually used at about 1 to about 2 mol per mol of Compound (XIII).
The ring-closure reaction and oxidation after the above reaction can be carried out in the absence of a solvent or in an inert solvent such as diphenylether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, xylene, toluene, etc., or a mixed solvent thereof, in the air (or under oxygen atmosphere) and in a temperature range from room temperature to about 300xc2x0 C. The reaction time is about 1 hour to about 10 hours.
(Process 4)
Compound (XIII) is reacted with an aminating agent and then with Compound (XVIII), followed by cyclization to produce ketone Compound (VI).
Said amination is carried out according to a method described in Process 2.
Condensation reaction after the reaction can be carried out in an inert solvent such as methanol, ethanol, benzene, toluene, chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethylether, hexane, ethyl acetate, dimethylformamide, dimethylsulfoxide, etc., or a mixed solvent thereof, and in a temperature range from about 0xc2x0 C. to about 100xc2x0 C. The reaction time is about 1 hour to about 50 hours. Compound (XVIII) is usually used at about 1 to about 2 mol per mol of Compound (XIII).
Ring-closure reaction after the reaction can be carried out in the absence of a solvent or in an inert solvent such as tetrahydrofuran, diphenylether, dimethoxyethane, methanol, ethanol, dichloromethane, chloroform, hexane, benzene, toluene, etc., or a mixed solvent thereof, and in a temperature range from about 50xc2x0 C. to about 300xc2x0 C. The reaction time is about 10 minutes to about 5 hours.
(Process 5)
Compound (VI) produced in Process 4 is halogenated to produce ketone Compound (VII) (wherein X is a halogen atom).
Said halogenation can be carried out by a known method. For example, when phosphorus oxychloride is used as a halogenating agent, about 1 to about 20 times of a halogenating agent is used and the reaction is carried out in the absence of a solvent or in an inert solvent such as tetrahydrofuran, dimethoxyethane, hexane, toluene, benzene, dichloromethane, chloroform, etc., or a mixed solvent thereof, and in a temperature range from about 0xc2x0 C. to about 150xc2x0 C. The reaction time is about 30 minutes to about 10 hours. This reaction can be facilitated by the addition of dimethylformamide, etc.
(Process 6)
Compound (VII) produced in Process 5 is reacted with Compound (XIX) to produce ketone Compound (VIII).
This reaction can be carried out in an inert solvent such as tetrahydrofuran, diethylether, dimethoxyethane, methanol, ethanol, hexane, toluene, benzene, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, etc., or a mixed solvent thereof, and in a temperature range from about 0xc2x0 C. to about 150xc2x0 C. The reaction time is about 30 minutes to about 50 hours. Compound (XIX) is usually used at about 1 to about 2 mol per mol of Compound (VII). If necessary, abase such as lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc. can be used for the reaction.
(Process 7)
Compound (XIII) is reacted with Compound (XX) and then with Compound (XXI) (wherein A-B is an optionally substituted hydrazine, hydroxylamine, etc.), followed by cyclization to produce ketone Compound (IX) or (IXxe2x80x2).
The condensation reaction can be carried out by a known method, for example, in the presence of a condensing agent such as DCC, WSC, etc., in an inert solvent such as tetrahydrofuran, diethylether, dimethoxyethane, dimethylformamide, dimethylsulfoxide, hexane, toluene, benzene, dichloromethane, chloroform, ethyl acetate, etc., or a mixed solvent thereof, and in a temperature range from about 0xc2x0 C. to about 150xc2x0 C. The reaction time is about 1 hour to about 50 hours. Compound (XX) is usually used at about 1 to about 3 mol per mol of Compound (XIII) and also used as a solvent.
Ring-closure reaction after the reaction can be carried out in an inert solvent such as tetrahydrofuran, diphenylether, dimethoxyethane, methanol, ethanol, hexane, toluene, benzene, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, etc., or a mixed solvent thereof, and in a temperature range from about 0xc2x0 C. to about 150xc2x0 C. The reaction time is about 1 hour to about 50 hours. Compound (XXI) is usually used at about 1 to about 2 mol per mol of Compound (XIII).
(Process 8)
Compound (XIII) is reacted with Compound (XXII) and then with Compound (XXIII), followed by cyclization to produce ketone Compound (X).
The condensation reaction is carried out according to similar condensation reaction described in Process 7.
Cyclization reaction after the reaction can be carried out in an inert solvent such as tetrahydrofuran, diphenylether, dimethoxyethane, methanol, ethanol, hexane, benzene, toluene, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, etc., or a mixed solvent thereof, and in a temperature range from about 0xc2x0 C. to about 150xc2x0 C. The reaction time is about 1 hour to about 100 hours. This reaction can be facilitated by reacting the first product obtained in the condensation reaction with an amine to produce an enamine derivative and reacting the enamine derivative with Compound (XXIII).
(Process 9)
Compound (XIII) is reacted with Compound (XXIV), followed by cyclization to produce ketone Compound (XI).
This condensation reaction can be carried out in an inert solvent such as tetrahydrofuran, diethylether, dimethoxyethane, methanol, ethanol, hexane, toluene, benzene, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, etc., or a mixed solvent thereof, in the presence of a base, and in a temperature range from about 0xc2x0 C. to about 100xc2x0 C. The reaction time is about 30 minutes to about 20 hours. As the base, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc. can be employed. Compound (XXIV) is usually used at about 1 to about 2 mol per mol of Compound (XIII).
Cyclization reaction after the reaction can be carried out in the absence of a solvent or in an inert solvent such as tetrahydrofuran, diphenylether, dimethoxyethane, methanol, ethanol, dimethylformamide, dimethylsulfoxide, xylene, toluene, dichloromethane, chloroform, etc., or a mixed solvent thereof, and in a temperature range from room temperature to about 300xc2x0 C. The reaction time is about 1 hour to about 50 hours.
(Process 10)
Compound (XIII) is halogenated and reacted with Na2S, etc., and then the obtained product is reacted with Compound (XXV), followed by cyclization to produce ketone Compound (XII).
The halogenation is carried out by a known method. For example, when phosphorus trichloride is used as a halogenating agent, about ⅓ to about 5 times mol of the halogenating agent is used and the reaction is carried out in the absence of a solvent or in an inert solvent such as tetrahydrofuran, dimethoxyethane, hexane, toluene, benzene, dichloromethane, chloroform, etc., or a mixed solvent thereof, and in a temperature range from about 0xc2x0 C. to about 150xc2x0 C. The reaction time is about 30 minutes to about 10 hours.
The reaction with Na2S, etc. is carried out in an inert solvent such as water, tetrahydrofuran, diethylether, dimethoxyethane, methanol, ethanol, hexane, toluene, benzene, dichloromethane, chloroform, etc., or a mixed solvent thereof, and in a temperature range from about 0xc2x0 C. to about 100xc2x0 C. The reaction time is about 30 minutes to about 10 hours.
This condensation reaction can be carried out in an inert solvent such as tetrahydrofuran, diethylether, dimethoxyethane, methanol, ethanol, hexane, toluene, benzene, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, etc., or a mixed solvent thereof, in the presence of a base, and in a temperature range from about 0xc2x0 C. to about 100xc2x0 C. The reaction time is about 30 minutes to about 20 hours. As the base, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc. can be employed. Compound (XXV) is usually used at about 1 to about 2 mol per mol of Compound (XIII).
Cyclization reaction after the reaction can be carried out in the absence of a solvent or in an inert solvent such as tetrahydrofuran, diphenylether, dimethoxyethane, methanol, ethanol, dimethylformamide, dimethylsulfoxide, xylene, toluene, dichloromethane, chloroform, etc., or a mixed solvent thereof, and in a temperature range from room temperature to about 300xc2x0 C. The reaction time is about 1 hour to about 100 hours.
(Process 11)
Compound (XIII) is reacted with Compound (XXVII) [wherein R21 is an optionally substituted phenyl such as phenyl, 4-methylphenyl, 4-methoxyphenyl, etc.] to produce a hydrazide derivative, which is reacted with Compound (XXVIII) in the presence of a base to produce ketone Compound (XXVI).
The reaction with Compound (XXVII) can be carried out in an inert solvent such as methanol, ethanol, toluene, benzene, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, diethylether, hexane, ethyl acetate, dimethylformamide, etc,., or a mixed solvent thereof, and in a temperature range from about 0xc2x0 C. to about 150xc2x0 C. The reaction time is about 1 hour to about 100 hours. Aminating agent is usually used at about 1 to about 10mol per mol of Compound (XIII).
The reaction with Compound (XXVIII) and cyclization reaction can be carried out in an inert solvent such as methanol, ethanol, toluene, benzene, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, diethylether, hexane, ethyl acetate, dimethylformamide, dimethylsulfoxide, etc., or a mixed solvent thereof, and in a temperature range from about 0xc2x0 C. to about 150xc2x0 C. The reaction time is about 1 hour to about 50 hours. As the base, potassium carbonate, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc. can be employed. Compound (XVIII) is usually used at about 1 to about 5 mol per mol of Compound (XIII).
The ketone compounds obtained in these Processes 1 to 11 can be used for the subsequent reaction without isolating or purifying.
In all of the above-mentioned processes, when the compounds have a carbonyl group, an amino group, a hydroxy group or a carboxyl group, these groups may be protected by ordinary protective groups introduced according to a conventional method. After the reaction, if necessary, the protective groups may be removed to obtain the desired compound.
Examples of the carbonyl-protective group include an optionally substituted cyclic or non-cyclic acetal or ketal, an optionally substituted cyclic or non-cyclic dithioacetal or dithioketal, etc.
Examples of the amino-protective group include a lower (C1-6) alkyl-carbonyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, etc.), benzoyl, etc.
Examples of the hydroxy-protective group include methoxydimethylmethyl, trimethylsilyl, t-butyldimethylsilyl, trimethylsilylethoxymethyl (SEM), methoxymethyl, benzyloxymethyl, tetrahydropyranyl (THP), etc.
Examples of the carboxyl-protective group include lower (C1-6)alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc.), C7-12 aralkyl (e.g. benzyl, phenethyl, 4-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl, etc.). In addition, the carboxyl group can be protected by transformation to 2-oxazoline ring.
These protective groups may be introduced or removed by per se known methods (e.g. a method described in Protective Groups in Organic Chemistry (J. F. W. McOmie et al.; Plenum Press Inc.) or the methods analogous thereto. For example, employable methods for removing the protective groups are methods using an acid, a base, reduction, ultraviolet ray, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc.
In the above Compound (I) or the starting material compound or synthesis intermediate thereof, basic compounds can be converted to salts using acid by a conventional method. The appropriate acid for this reaction is preferably an acid capable of providing a pharmacologically acceptable salt. Examples of such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid or sulfamic acid, etc., and organic acids such as acetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, p-toluenesulfonic acid, methanesulfonic acid, glutamic acid or pyroglutamic acid, etc. When the compound obtained is a salt, it may be converted to a free base by a conventional method.
In the above Compound (I) or the starting material compound or synthesis intermediate thereof, acidic compounds having an acidic group such as xe2x80x94COOH, etc. can be converted to salts by a conventional method. Preferable examples of the salts include salts with alkali metal, alkaline earth metal, ammonium, substituted ammonium, etc., more specifically exemplified by salts with sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, tri-C1-6 alkylammonium (e.g. trimethylammonium, triethylammonium, etc.), triethanolammonium, etc.
Unless otherwise stated, the above reactions are each carried out using the starting material normally in an equimolar amount, reaction time being normally 1 to 24 hours.
The thus-obtained Compound (I) or starting material compound thereof may be isolated from the reaction mixture by ordinary means of separation and purification such as extraction, concentration, neutralization, filtration, crystallization, recrystallization, column (or thin layer) chromatography, etc.
Naxe2x80x94H exchange inhibitor of the present invention which comprises Compound (I) exhibits excellent cell disorder ameliorating activity or cell-protecting activity (especially on the myocardium) in animals, especially mammals (for example, human, monkey, swine, dog, cat, rabbit, guinea pig, rat, mouse, etc.) and is useful as an agent for the prevention or treatment of ischemic disease (for example, ischemic cardiac disease, etc. such as myocardial infarction and dysfunctions accompanying thereto, unstable angina, etc.), restenosis after PTCA, arrhythmia, cardiac insufficiency, hypercardia, hypertension and tissue disorders accompanying thereto, ischemic encephalic disease (for example, cerebral infarction, cerebral hemorrhage, cerebral disorders accompanying to subarachnoid hemorrhage, etc.) (preferably, an agent for the prevention or treatment of ischemic cardiac disease such as myocardial infarction and dysfunctions accompanying thereto, unstable angina, etc., restenosis after PTCA, arrhythmia, cardiac insufficiency, hypercardia, etc.; more preferably an agent for the prevention or treatment of ischemic cardiac disease such as myocardial infarction, etc., cardiac insufficiency, etc.). Here, conception of the prevention of cardiac insufficiency includes the treatment of prognosis of myocardial infarction. Also, conception of the treatment of cardiac insufficiency includes inhibition of evolution or grade of cardiac insufficiency, etc.
The Compound (I) used as an active ingredient in the present invention is of low toxicity, shows good absorbability when orally administered and is superior in stability, and therefore, it can be orally or non-orally safely administered as such, or as pharmaceutical compositions such as powders, granules, tablets, capsules (including soft capsules, microcapsule), liquid preparations, injections, suppositories, etc. in combination with an appropriate pharmaceutically acceptable carrier, excipient, diluent, etc., when used as an agent as described above.
Naxe2x80x94H exchange inhibitor and pharmaceutical composition of the present invention can be prepared as pharmaceutical preparations by ordinary methods. The content ratio of Compound (I) in the pharmaceutical composition of the present invention is about 0.01 to about 20% (W/W).
In the present specification, xe2x80x9cnon-oralxe2x80x9d includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion, etc.
Injectable preparations, for example, aqueous or oily suspensions for aseptic injection, can be prepared by methods known in relevant fields, using an appropriate dispersing agent or wetting agent and a suspending agent. The aseptic injectable preparation may be an aseptically injectable solution or suspension in a diluent or solvent which permits non-toxic non-oral administration, such as an aqueous solution, etc. Acceptable vehicles or solvents include water, Ringer""s solution, isotonic saline, etc. It is also possible to use aseptic non-volatile oils in common use as solvents or suspending media. For this purpose, any non-volatile oil or fatty acid can be used, including natural, synthetic or semi-synthetic fatty oils or fatty acids, and natural, synthetic or semi-synthetic mono-, di- or tri-glycerides.
Suppositories for rectal administration may be produced as a mixture of the drug and an appropriate non-irritative shaping agent, such as cacao butter or polyethylene glycol, which is solid at normal temperatures and which is liquid at intestinal temperatures and melts and releases the drug in the rectum.
Solid dosage form for oral administration include the above-mentioned forms such as powders, granules, tablets, pills, capsules, etc. In these dosage form, the active ingredient compound may be mixed with at least one additive such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginate, chitin, chitosan, pectin, gum traganth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymer or glyceride. Such dosage forms may contain the usual additional additives, including inert diluents, lubricants such as magnesium stearate, etc., preservatives such as paraben, sorbic acid, etc., antioxidants such as ascorbic acid, xcex1-tocopherol, cysteine, etc., disintegrating agents, binders, thickening agents, buffers, sweeteners, flavoring agents, perfumes, etc. Tablets and pills may be produced with enteric coating.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions, etc., which may contain inert diluents, such as water, in common use in relevant fields.
Although varying depending on the subject of administration, route of administration and symptoms, the dose is normally about 0.005 to 10 mg/kg, preferably 0.01 to 5 mg/kg, and more preferably about 0.02 to 1 mg/kg (about 0.3 to 600 mg/man, preferably 0.6 to 300 mg/man, and more preferably 1.2 to 60 mg/man), based on Compound (I), per administration in the case of oral administration in a patient (adult weighing about 60 kg) with myocardial infarction. It is desirable that such dosage be given about 1 to 3 times per day, depending on symptoms. In acute onset of disease, e.g., just after onset of myocardial infarction, higher doses and especially higher dosing frequencies, e.g., 4 administrations per day, may be necessary. In the case of a patient with myocardial infarction under intensive care treatment, in particular, about 100 mg/man per day may be necessary for intravenous administration.
By using Compound (I) of the present invention in combination with a compound having endothelin antagonistic activity or a salt thereof, Compound (I) can perform remarkable effects in the prevention or treatment of ischemic diseases, especially ischemic cardiac disease, and in particular, myocardial infarction, cardiac insufficiency, arrhythmia, etc., and cover up defects observed in administration of a medicine consisting of a single component. For example, Compound (I) combined with a compound having endothelin antagonistic activity or a salt thereof performs especially remarkable effects (e.g. treatment effect, safety, stability, dose, administration route, method of use, etc.) which were not observed in the administration of the respective compounds singly.
Examples of the compound having endothelin antagonistic activity or a salt thereof include, for example, compounds described in EP-A-552489, EP-A-528312, EP-A-499266, W091/13089, EP-A-436189, EP-A-457195, EP-A-510526, W092/12991, Japanese Patent Unexamined Publication No. 288099/1992, Japanese Patent Unexamined Publication No. 244097/1992, Japanese Patent Unexamined Publication No. 261198/1992, EP-A-496452, EP-A-526708, EP-A-526642, EP-A-510526, EP-A-460679, W092/20706, EP-A-626174, EP-A-655463, EP-A-714909, Japanese Patent Unexamined Publication No. 1995 (H7)-173161, etc. Among others, the following compounds are preferably employed:
disodium salt of Cyclo[-D-Asp-Asp (R1)-Asp-D-Thg(2)-Leu-D-Trp-], in which Asp (R1) is aspartic acid xcex2-4-phenylpiperazineamide residue and Thg(2) is 2-thienylglycine residue (hereinbelow, referred to as Compound A); 
Among others, Cyclo[-D-Asp-Asp (R1)-Asp-D-Thg(2)-Leu-D-Trp] in which Asp (R1) is aspartic acid xcex2-4-phenylpiperazineamide residue and Thg(2) is 2-thienylglycine residue, or a salt thereof is preferable, and in particular, 2Na salt of Cyclo[-D-Asp-Asp (R1)-Asp-D-Thg(2)-Leu-D-Trp-], in which Asp (R1) is aspartic acid xcex2-4-phenylpiperazineamide residue and Thg(2) is 2-thienylglycine residue, is preferable.
To state further, in the case of using the compound having endothelin antagonistic activity or a salt thereof in combination with the Compound (I) having activity for inhibiting Naxe2x80x94H exchange, these drugs can be formulated by mixing individually or simultaneously with pharmaceutically acceptable carriers, excipients, binders, diluents, etc., which can be administered orally or non-orally as a pharmaceutical composition. In the case of formulating these effective components individually, while the individually formulated agents can be administered in the form of their mixture prepared by using e.g. a diluent when administered, the individually formulated agents can also be administered separately or simultaneously or with time intervals to the one and same subject. A kit for administering the individually formulated effective components in the form of their mixture prepared by using e.g. a diluent when administered (e.g. a kit for injection which comprises two or more ampoules each comprising a powdery component and a diluent for mixing and dissolving two or more components when administered, etc.), a kit for administering the individually formulated agents simultaneously or with time intervals to the one and the same subject (e.g. a kit for tablets to be administered simultaneously or with time intervals, characterized by having two or more tablets each comprising an agent and said tablets being put in one or separate bags and, if necessary, a column to describe the time each agent is to be administered, etc.), etc. are also included by the pharmaceutical composition of the present invention.
When the compound having endothelin antagonistic activity or a salt thereof is used in combination with the Compound (I) having activity for inhibiting Naxe2x80x94H exchange, the dose of individual drugs is determined in accordance with the minimal recommendable clinical dose of individual drugs, and can be selected dependent on the subject, age, body weight, symptom, dose interval, administration route, type of formulation, combination of drugs, etc.
The dose to be administered to a specific patient is dependent on the age, body weight, general health conditions, sex, diet, dose interval, administration route, excretion rate, combination of drugs, conditions of the disease then treated, other factors, etc.
Typical daily dose of combination of the compound having endothelin antagonistic activity or a salt thereof with the compound (I) having activity for inhibiting Naxe2x80x94H exchange is within the range of from about {fraction (1/50)} of the minimal recommendable clinical dose to the maximum recommendable clinical dose (preferably from minimal recommendable clinical dose or less, more preferably xc2xd of minimal recommendable clinical dose or less) in the case of practical administration of these compounds individually.
For example, in case of the treatment of myocardial infarction in human adult (body weight: about 60 kg) by oral administration, a single dose of the compound having activity for inhibiting Naxe2x80x94H exchange usually ranges from about 0. 002 to about 5 mg/kg, preferably from 0.005 to 2 mg/kg, more preferably from 0.02 to 1 mg/kg, and it is desirable that such dosage is given about once to about 3 times a day, depending on symptoms. In acute onset of disease, for example, just after myocardial infarction, higher dose and especially higher dosing frequencies, for, example, 4 times a day, may be necessary. In particular, in the case of a patient with myocardial infarction under intensive care treatment, about 50 mg/patient per day may be necessary for intravenous administration.
On the other hand, the dose ranging from about 10-300 mg/human/day (preferably, about 20-200 mg/human/day, more preferably, about 50-100 mg/human/day) of the endothelin antagonist (preferably by intravenous administration) is effectively combined with the Naxe2x80x94H exchange inhibitor. Needless to state, while these dosage ranges can be adjusted by a necessary unit base for dividing a daily dose, such doses are decided by taking into consideration the diseases to be treated, conditions of such disease, the age, body weight, general health conditions, sex, diet, dose intervals, administration route, excretion rate, combination of drugs, and other factors.
The present invention is hereinafter described in more detail by means of the following Reference Examples of starting material production and Working Examples of Compound (I) production, which are not to be construed as limitative. In the present specification, room temperature means 0 to 25xc2x0 C. and the abbreviations used are defined as follows: